Transport of the renal carcinogen 3-hydroxymethyl-1-([3-(5-nitro-2-furyl)allydidene]amino) hydantoin by renal cortex and cooxidative metabolism by prostaglandin endoperoxide synthetase.
Transport of the renal carcinogen 3-hydroxymethyl-1-([3-(5-nitro-2-furyl)-allydidene]amino) hydantoin (HMN) by the renal cortex and metabolism by the kidney was evaluated. Organic acid and base transport by renal cortical slices was determined using [131I]Hippuran and [14C]tetraethylammonium, respectively. HMN caused a dose-dependent reversible inhibition of [131]Hippuran accumulation but did not alter [14C]tetraethylammonium uptake. By contrast, benzidine inhibited organic base but not acid transport. The decrease in absorbance at 405 nm was used as an index of microsomal metabolism of HMN. Reduced nicotinamide adenine dinucleotide phosphate-dependent metabolism of HMN was not observed with either cortical or medullary microsomes. However, there was prostaglandin endoperoxide synthetase-mediated metabolism of HMN. Specific substrate, cofactor, and inhibitor studies suggest that metabolism occurs by the prostaglandin hydroperoxidase activity of prostaglandin endoperoxide synthetase. At least one product of HMN metabolism was characterized and shown to be different from HMN by its high-pressure liquid chromatographic and ultraviolet spectral properties. The renal mixed-function oxidases system, lipid peroxidation, nitroreduction, and lipoxygenase did not seem to be involved in HMN metabolism. These results are consistent with the hypothesis that the kidney is a site for cooxidative metabolism of chemicals which elicit carcinogenic and nephrotoxic effects in the kidney. Facilitated transport of HMN into renal tissue by the organic acid transport system may explain the greater potential for HMN to elicit renal carcinogenesis compared to other tissues.
D000818:Animals; D001692:Biological Transport; D002273:Carcinogens; D002851:Chromatography, High Pressure Liquid; D006827:Hydantoins / Q000378:metabolism*; D066298:In Vitro Techniques; D007465:Iodohippuric Acid / Q000378:metabolism; D007672:Kidney Cortex / Q000378:metabolism*; D007679:Kidney Medulla / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000378:metabolism; D009581:Nitrofurans / Q000378:metabolism*; D010084:Oxidation-Reduction; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011817:Rabbits; D013757:Tetraethylammonium Compounds / Q000378:metabolism
D002273:Carcinogens; D006827:Hydantoins; D009581:Nitrofurans; D013757:Tetraethylammonium Compounds; D007465:Iodohippuric Acid; D011451:Prostaglandin-Endoperoxide Synthases; C008050:nifurmazole